In an effort to decipher the cellular dysfunction underlying Alzheimer's Disease (AD), transgenic (Tg) animal technology has been used to generate mouse strains that model aspects of the human disease. These models target the known autosomal dominant familial AD risk factors in order to model the amyloidogenesis- associated abnormalities observed in AD brain. This proposal utilizes a Tg mouse model for AD in which the transgene is the human 695 splice-variant of APP that contains the double mutation K670M, N671L driven by a hamster prion protein gene promoter. (This APP mutation was identified in a Swedish family with inherited AD). This is our AD mouse model of choice as this Tg mouse strain (Tg2576) approximates many of the pathological correlates of AD and, as importantly, is well characterized in several respects. We will use this model to characterize effects of overexpression of mutant APP in the mouse brain, especially as related to the signal transduction mechanisms subserving hippocampal synaptic plasticity and learning. Specific Aim number 1 - To test the hypothesis that hippocampal MAPK activation is aberrant in Tg2576 mice. It is our prediction that the chronic exposure of neurons to elevated levels of extracellular Abeta that occurs in Tg2576 mice affects p42 MAPK regulation. Specific Aim number 2 - To test the hypothesis that aberrant p42 MAPK activity underlies LTP deficits in Tg2576 mice. p42 MAPK is activated in LTP and this is necessary for LTP. We expect to find evidence for an interruption in p42 MAPK signaling following induction of CA1 LTP since hippocampal slices from aged Tg2576 mice fail to express this form of potentiation. Specific Aim number 3 - To test the hypothesis that the hippocampus- dependent associative learning impairment exhibited by Tg2576 is accompanied by deficits in hippocampal signaling mechanisms. Hippocampal MAPK is activated with fear conditioning. We will evaluate if this activation is altered in Tg2576 mice. Overall, these studies will yield new insights into the sequelae of mutant APP overproduction in the CNS.